Harm reduction programs provide tools that enable people who use drugs to do so more safely in a nonstigmatizing environment without the goal of them necessarily seeking treatment or abstinence. Most harm reduction programs in the United States distribute sterile syringes and naloxone and safely dispose of used syringes and other drug use supplies. Many also provide drug checking services, and other safer use supplies. These programs exist on a limited scale and often face restrictions on their funding and scope of operations. While research demonstrates the effectiveness of existing programs in preventing infectious disease transmission and fatal overdose, there is less evidence about conditions that support the effective expansion and sustainment of existing models. Other harm reduction interventions such as overdose prevention centers and safer supply programs have promising international evidence but are prohibited or severely restricted under US law. In this review, we summarize the evidence for harm reduction interventions, describe the policy environment in which they exist, and provide recommendations to better align drug policy with existing and emerging evidence in the US context.